Small cell lung cancer: from molecular biology to novel therapeutics

Pisick, Evan; Jagadeesh, Simha; Salgia, Ravi

doi:10.1111/j.1533-869x.2003.01103.x

Cited by 15 publications

(13 citation statements)

References 118 publications

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“…SCLC exhibits aggressive cell growth leading to very poor clinical prognosis, although it is also characterized by large areas of necrosis (36) and cell lines are difficult to establish (37). The putative growth disadvantage due to low POLD4 might be partially compromised by the characteristics of SCLC.…”

Section: Discussionmentioning

confidence: 99%

Regulation of DNA Polymerase POLD4 Influences Genomic Instability in Lung Cancer

et al. 2010

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Genomic instability is an important factor in cancer susceptibility, but a mechanistic understanding of how it arises remains unclear. We examined hypothesized contributions of the replicative DNA polymerase δ (pol δ) subunit POLD4 to the generation of genomic instability in lung cancer. In examinations of 158 lung cancers and 5 mixtures of 10 normal lungs, cell cycle-and checkpoint-related genes generally showed mRNA expression increases in cancer, whereas POLD4 showed reduced mRNA in small cell lung cancer (SCLC). A fraction of non-small cell lung cancer patients also showed low expression comparable with that in SCLC, which was associated with poor prognosis. The lung cancer cell line ACC-LC-48 was found to have low POLD4 expression, with higher histone H3K9 methylation and lower acetylation in the POLD4 promoter, as compared with the A549 cell line with high POLD4 expression. In the absence of POLD4, pol δ exhibited impaired in vitro DNA synthesis activity. Augmenting POLD4 expression in cells where it was attenuated altered the sensitivity to the chemical carcinogen 4-nitroquinoline-1-oxide. Conversely, siRNA-mediated reduction of POLD4 in cells with abundant expression resulted in a cell cycle delay, checkpoint activation, and an elevated frequency of chromosomal gap/break formation. Overexpression of an engineered POLD4 carrying silent mutations at the siRNA target site rescued these phenotypes, firmly establishing the role of POLD4 in these effects. Furthermore, POLD4 overexpression reduced intrinsically high induction of γ-H2AX, a well-accepted marker of double-stranded DNA breaks. Together, our findings suggest that reduced expression of POLD4 plays a role in genomic instability in lung cancer. Cancer Res; 70(21); 8407-16. ©2010 AACR.

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Section: Discussionmentioning

confidence: 99%

Regulation of DNA Polymerase POLD4 Influences Genomic Instability in Lung Cancer

et al. 2010

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“…Therefore, a possible explanation for the present findings is that the expression of the drs gene is downregulated by the activation of endogenous oncogenes in SCLC. In fact, it has been reported that myc is overexpressed by gene amplification in SCLC (5). Loss of heterozygosity (LOH) of PTEN, which activates Akt, was also frequently observed in SCLC cell lines (4).…”

Section: Discussionmentioning

confidence: 99%

“…Almost all carcinoid tumors in the lung show few symptoms, and they are rarely resected. Studies of the genetic alterations of proto-oncogenes and tumor suppressor genes, including myc, PTEN, p53, and Rb, in SCLC have been performed (4)(5)(6). Various genetic changes such as chromosomal loss, mutations, and methylation were also reported for other carcinoid tumors, including TC, AC, and LCNEC (7)(8)(9)(10)(11)(12).…”

Section: Introductionmentioning

confidence: 99%

Downregulation of drs tumor suppressor gene in highly malignant human pulmonary neuroendocrine tumors

Shimakage¹

2009

Oncol Rep

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Abstract. Neuroendocrine tumors in the lung fall into four categories: typical carcinoid tumor (TC), atypical carcinoid tumor (AC), large-cell neuroendocrine carcinoma (LCNEC) and small-cell lung carcinoma (SCLC), in ascending order of malignancy. The drs gene was originally isolated as a suppressor against v-src transformation and was shown to induce apoptosis in human cancer cells. The expression of drs was markedly downregulated in various human cancer tissues and cell lines. Furthermore, drs knockout mice showed a tumor-prone phenotype, indicating that drs acts as a tumor suppressor gene in malignant tumor formation. To clarify the role of the drs gene in the development of human pulmonary neuroendocrine tumors, we examined the expression of drs mRNA in tissue specimens from 3 cases of TC, 4 cases of AC, 2 cases of LCNEC, and 11 cases of SCLC by in situ mRNA hybridization. Four cases of normal lung and bronchial epithelia, 8 samples of normal brain tissue, and 2 cases of tumorlets in the lung were also examined. The drs mRNA was definitely expressed in all normal tissues of the lung and brain, and 3 TC and 2 tumorlet tissues. The expression of drs mRNA was also detected in 2 of 2 LCNEC tissues and 3 of 4 AC tissues, although the signals were weak. On the other hand, drs mRNA was not detected in 10 of 11 SCLC tissues. Downregulation of drs mRNA was also observed in 3 of 4 SCLC cell lines that were examined by reverse transcriptasepolymerase chain reaction (RT-PCR). Neither gross deletion nor rearrangement of the drs genome was detected in these cell lines by Southern blot analysis. Our results indicate that the downregulation of drs is correlated with the development of SCLC, a highly malignant pulmonary neuroendocrine tumor.

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“…Metastases develop quickly, primarily to bone marrow and brain, and are usually present at the time of diagnosis. In untreated patients, median survival is two months from the onset of symptoms [1].…”

Section: Introductionmentioning

confidence: 99%

Identification of uPAR-positive Chemoresistant Cells in Small Cell Lung Cancer

et al. 2007

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BackgroundThe urokinase plasminogen activator (uPA) and its receptor (uPAR/CD87) are major regulators of extracellular matrix degradation and are involved in cell migration and invasion under physiological and pathological conditions. The uPA/uPAR system has been of great interest in cancer research because it is involved in the development of most invasive cancer phenotypes and is a strong predictor of poor patient survival. However, little is known about the role of uPA/uPAR in small cell lung cancer (SCLC), the most aggressive type of lung cancer. We therefore determined whether uPA and uPAR are involved in generation of drug resistant SCLC cell phenotype.Methods and FindingsWe screened six human SCLC cell lines for surface markers for putative stem and cancer cells. We used fluorescence-activated cell sorting (FACS), fluorescence microscopy and clonogenic assays to demonstrate uPAR expression in a subpopulation of cells derived from primary and metastatic SCLC cell lines. Cytotoxic assays were used to determine the sensitivity of uPAR-positive and uPAR-negative cells to chemotherapeutic agents. The uPAR-positive cells in all SCLC lines demonstrated multi-drug resistance, high clonogenic activity and co-expression of CD44 and MDR1, putative cancer stem cell markers.ConclusionsThese data suggest that uPAR-positive cells may define a functionally important population of cancer cells in SCLC, which are resistant to traditional chemotherapies, and could serve as critical targets for more effective therapeutic interventions in SCLC.

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Small cell lung cancer: from molecular biology to novel therapeutics

Cited by 15 publications

References 118 publications

Regulation of DNA Polymerase POLD4 Influences Genomic Instability in Lung Cancer

Regulation of DNA Polymerase POLD4 Influences Genomic Instability in Lung Cancer

Downregulation of drs tumor suppressor gene in highly malignant human pulmonary neuroendocrine tumors

Identification of uPAR-positive Chemoresistant Cells in Small Cell Lung Cancer

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